Kidney-targeted Birt-Hogg-Dubé gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys

Masaya Baba, Mutsuo Furihata, Seung Beom Hong, Lino Tessarollo, Diana C. Haines, Eileen Southon, Vishal Patel, Peter Igarashi, W. Gregory Alvord, Robert Leighty, Masahiro Yao, Marcelino Bernardo, Lilia Ileva, Peter Choyke, Michelle B. Warren, Berton Zbar, W. Marston Linehan, Laura S. Schmidt

Research output: Contribution to journalArticlepeer-review

206 Scopus citations


Background: Patients with Birt-Hogg-Dubé (BHD) syndrome harbor germline mutations in the BHD tumor suppressor gene that are associated with an increased risk for kidney cancer. BHD encodes folliculin, a protein that may interact with the energy- and nutrient-sensing 5′-AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling pathways. Methods: We used recombineering methods to generate mice with a conditional BHD allele and introduced the cadherin 16 (KSP)-Cre transgene to target BHD inactivation to the kidney. Kidney cell proliferation was measured by BrdU incorporation and phospho-histone H3 staining. Kidney weight data were analyzed with Wilcoxon's rank-sum, Student's t, and Welch's t tests. Hematoxylin and eosin staining and immunoblot analysis and immunohistochemistry of cell cycle and signaling proteins were performed on mouse kidney cells and tissues. BHD knockout mice and kidney cells isolated from BHD knockout and control mice were treated with the mTOR inhibitor rapamycin. Mouse survival was evaluated by Kaplan-Meier analyses. All statistical tests were two-sided. Results: BHD knockout mice developed enlarged polycystic kidneys and died from renal failure by 3 weeks of age. Targeted BHD knockout led to the activation of Raf-extracellular signal-regulated protein kinase (Erk)1/2 and Akt-mTOR pathways in the kidneys and increased expression of cell cycle proteins and cell proliferation. Rapamycin-treated BHD knockout mice had smaller kidneys than buffer-treated BHD knockout mice had (n = 4-6 mice per group, relative kidney/body weight ratios, mean = 4.64% vs 12.2%, difference = 7.6%, 95% confidence interval = 5.2% to 10.0%; P <. 001) and longer median survival time (n = 4-5 mice per group, 41.5 vs 23 days; P =. 0065). Conclusions: Homozygous loss of BHD may initiate renal tumorigenesis in the mouse. The conditional BHD knockout mouse may be a useful research model for dissecting multistep kidney carcinogenesis, and rapamycin may be considered as a potential treatment for Birt-Hogg-Dubé syndrome.

Original languageEnglish (US)
Pages (from-to)140-154
Number of pages15
JournalJournal of the National Cancer Institute
Issue number2
StatePublished - Jan 2008

Bibliographical note

Funding Information:
We thank Louise Cromwell for excellent technical support with the mouse studies, Mary Ellen Palko for helpful discussions regarding recombineer-ing methodology, and Tim Back for his technical expertise and discussions regarding mouse surgical procedures. We thank Maria Merino for informative, in-depth discussions of comparative human/mouse normal and abnormal histopathology and Octavio Quinones for support in producing some descriptive statistics and graphs and acknowledge the support provided to V. Patel and P. Igarshi by the University of Texas Southwestern O’ Brien Kidney Research Core Centre.

Funding Information:
Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health (N01 C012400, P30DK079328 and R01 DK067565 to P.I. ).


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